Precision in dosing infused anaesthetic agents has the advantage of providing adequate operating conditions in each patient, avoiding unwanted unconsciousness in sedated patients, avoiding respiratory arrest and severe hypotension in anaesthetized patients and particularly, avoiding awareness where unconsciousness is desired. The conventional approach to determining the bolus and variable infusion rate required to achieve a nominated target blood level is to derive a compartmental pharmacokinetic model following the administration of a single dose.
In U.S. Pat. No. 4,741,732 to Crankshaw et al and Austrailian Patent No. AU-B-42019/85 to The University of Melbourne the entire contents of both documents being hereby incorporated by cross-reference, there is described a plasma drug efflux method to determine infusion rates of a given drug to achieve a constant concentration necessary to achieve an effect in the patient. The present applicant has shown for a number of drugs that the infusion rate required to achieve a therapeutic effect differs to a considerable extent from the prediction made from giving a single dose of each of these drugs. there is also described in subsequent U.S. Pat. No. 5,034,004 Crankshaw et al improvements in a device to administer drugs intravenously, particularly during anaesthesia.
In summary, the disclosures of U.S. Pat. No. 4,441,732 and Australian Patent 42019/85 show that:
1. The rate of elimination of drugs from the blood is expressed as the volume of blood from which drug is removed each minute (liters/minute), and varies with time as it depends on the rate of elimination from the body plus the accumulation of drug in the body. PA0 2. The rate of elimination modified by the presence of the drug which influences both the elimination and the accumulation of the drug. PA0 3. The net effect of all these factors is a time varying measure of the rate of removal of the drug we term Plasma Drug Efflux (Ep). PA0 4. Ep is determined at a single drug concentration. This concentration is chosen as the mid-point within the range of concentrations normally used during anaesthesia. PA0 5. To maintain a specific target concentration (Ct) of the drug, the expected rate of loss of drug from the circulation is calculated by multiplying Ep (litres/min) by Ct (mg/liter), PA0 6. The rate of loss (Q mg/min) equals the rate at which drugs must be administered to maintain to constant concentration, and as Ep varies with time, Q varies with time in direct proportion. PA0 7. The value of Ep is stored in the control system of the syringe pump as a single infusion rate profile for each drug to permit the generation of Q for each value of Ct. PA0 (i) calculating a multiplicity of infusion rate profiles for a selected agent by monitoring drug efflux from the body of a group of patients for a corresponding multiplicity of target concentrations of the selected agent, said multiplicity of infusion rate profiles including at least a set of profiles which cause the induction of light, average and deep anaesthesia in the patient, PA0 (ii) determining the body size of the patient, such as their Lean Body Mass; PA0 (iii) selecting a target concentration of the agent to in turn cause selection from the multiplicity of infusion rate profiles an infusion rate profile substantially corresponding to the infusion rate profile for the selected target concentration; PA0 (iv) scaling the selected infusion rate profile by the determined body size or Lean Body Mass of the patient, and PA0 (v) administering the agent to the patient in accordance with the scaled profile by means of an infusion device which is controlled to deliver said agent at said scaled infusion rate profile. PA0 (a) infusing a drug at arbitrary but known rates into a group of patients for each of whom the Lean Body Mass has been determined; PA0 (b) determining the plasma arterial concentration of the drug in each patient at a number of specific time intervals throughout each infusion period; PA0 (c) for each patient, estimating the rates of loss of drug from the circulation at a number of specific time instants by dividing the known infusion rates per Lean Body Mass of these instants by the plasma arterial concentrations of the drug at each of these instants; PA0 (d) calculating the average of the estimated rates of loss of drug from the circulation per Lean Body Mass unit at each specific time interval for the group of patients; PA0 (e) interpolating the successive average points between the specific time intervals to produce an infusion profile; PA0 (f) infusing said drug in accordance with said infusion profile determined from said interpolations into a group of patients for each of whom the Lean Body Mass has been determined, said infusion rate being scaled according to said Lean Body Mass of each patient, and PA0 (f) repeating steps (b) to (f) until a desired steady plasma arterial content of the drug is substantially maintained throughout the infusion period.
Since this original disclosure, the applicant has noted that, for anaesthetic agents, a number of concentrations can be defined which produce different therapeutic effects, for example:
(a) sedation where the subject is drowsy but not fully unconscious
(b) lightly anaesthetized where another drug such a nitrous oxide is required to achieve complete anaesthesia
(c) moderately anaesthetized when the drug alone produces anaesthesia
(d) deeply anaesthetized when the high concentration of the drug is used to achieve effects as well as anaesthesia, such as lowering of the arterial blood pressure or protection of the brain from lack of oxygen.
When evaluating the ability to implement plasma drug efflux rate profiles obtained according to the method of U.S. Pat. No. 4,471,732 at a number of different desired or target concentrations (C.sub.T), the applicant has found, particularly with the anaesthetic agent propofol, that the infusion rates required to maintain a constant concentration at each of these different clinically useful concentrations are not in direct proportion to each other. Thus as a result of observation of the method of the U.S. patent it has been determined that Ep during sedation for light anaesthesia, average anaesthesia and deep anaesthesia, does not remain constant in the case of Propofol, and both the size and the shape of the Ep curve varies for different levels of anaesthesia. This new observation that Ep is concentration dependant and that the simple proportion described in the U.S. patent does not apply means that in the case of propofol the amount of blood from which drug is removed actually falls as the concentration of the drug increases. The magnitude of this fall is such that Ep determined during sedation is approximately twice that determined during average anaesthesia, so that if a single Ep curve, determined during sedation, were used to calculate the infusion rate for average anaesthesia, an infusion rate of close to 100% higher than required to maintain Ct could result and overdose would occur. Similarly, if the Ep curve, determined during average anaesthesia, were used to generate the infusion rate to achieve sedation the infusion ration would be half that required and inadequate drug effect would result. As well, for a given value of Ct the presence of the anaesthetic nitrous oxide reduces the values of Ep when compared with the absence of nitrous oxide.
To summarize the above while the method of proportional adjustment of the infusion rate (U.S. Pat. No. 4,741,732, FIG. 7 ) is suitable for a number of agents, it is not suitable for adjusting the target concentration of drugs where non-linearity is apparent. Similarly, the required rate of infusion at any of these clinically useful concentrations may be altered considerably if a second anaesthetic agent, such as nitrous oxide is given at the same time. This observation means that if, for example nitrous oxide is added to the patient or removed at any time an adjustment must be made in the infusion rate profile to account for this.
While the invention is most preferably used with the drug efflux method of drug infusion profile generation described in U.S. Pat. No. 4,741,732, it is equally applicable to other methods of generating similar, albeit less effective, profiles. For example, it is possible to produce a family of profiles similar to the profiles produced by the method of the above U.S. patent by using a multi-compartment pharmaco-kinetic model used in the papers by Kruger-Theimer, and the other authors referred to in the introduction of the above U.S. patent, and manipulating the parameters of the model until profiles bearing some similarity to those produced by the method of the above U.S. patent are produced.